2qj9

File:2qj9.jpg

Crystal structure analysis of BMP-2 in complex with BMPR-IA variant B1

OverviewOverview

Bone morphogenetic proteins regulate many developmental processes during embryogenesis as well as tissue homeostasis in the adult. Signaling of BMPs is accomplished by binding to two types of serine/threonine kinase transmembrane receptors termed type I and type II. Since a large number of ligands signal through a limited number of receptors, ligand-receptor interaction in the BMP superfamily is highly promiscuous with a ligand binding to various receptors and a receptor binding many different BMP ligands. In this study we investigate the interaction of BMP-2 with its two high affinity type I receptors BMPR-IA and BMPR-IB. Interestingly, 50% of the residues in the BMP-2 binding epitope of BMPR-IA are exchanged in BMPR-IB without decrease in binding affinity or specificity for BMP-2. Our structural and functional analyses show that promiscuous binding of BMP-2 to both type I receptors is achieved by inherent backbone and sidechain flexibility as well as by variable hydration of the ligand-receptor interface enabling the BMP-2 surface to adapt to different receptor geometries. Despite the high degree of amino acid variability found between BMPR-IA and BMPR-IB, three single point missense mutations in the ectodomain of BMPR-IA found in juvenile polyposis syndrome result in inactivation of BMPR-IA. On the basis of our biochemical and biophysical analyses we can show that the mutations, which are located outside the ligand binding epitope alter the local or global fold of the receptor thereby inactivating BMPR-IA and causing a loss of the BMP-2 tumor suppressor function in colon epithelial cells.

About this StructureAbout this Structure

2QJ9 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.

ReferenceReference

Structure analysis of BMP-2 type I receptor complexes reveals a mechanism of receptor inactivation in juvenile polyposis syndrome., Kotzsch A, Nickel J, Seher A, Heinecke K, van Geersdaele L, Herrmann T, Sebald W, Mueller TD, J Biol Chem. 2007 Dec 26;. PMID:18160401 Page seeded by OCA on Sun May 4 15:03:06 2008